Thursday, March 10, 2005

Through the k-hole

What do squat parties in Brixton, vetinarians in Buckinghamshire, and cereals in Budgens have in common?* The answer, of course, is Special K.**

Ketamine is a tranquillising agent that was widely used until patients began to complain of its hallucinogenic effects, which they experienced when coming out of sedation. Not too fun. Except, of course, for those who take it for pleasure - of whom, according to ongoing research by Mixmag magazine and the Institute of Psychiatry, there have been more than a fourfold increase between 1999 and 2003. Apart from this population, the drug is still administered as a tranquilliser for animals, and also young children for whom the trippy effects don't seem to occur. Notably, after Putin banned the drug in Russia in 2003, Bridget Bardot campaigned for a reversal, on the basis that it would result in more suffering for animals; whether the implications for children were weighed is not on record, but in any case Russia reversed the ban in '04. Notably, the drug is not illegal in the EU, and whilst a controlled substance is low down in priority, at least in the eyes of the law. But if you're an ocassional taker, or curious about it, I suggest you read further, to get the skinny on the cognitive neuropsychopharmacology of ketamine.

My friend and colleague Celia Morgan has been doing her PhD on the cognitive effects of ketamine with Val Curran at UCL; Prof Curran gave a presentation about this last month; again, some is not yet published (although some is, and if you use Google Scholar you should be able to get your hands on some abstracts, at least).

To give the basic neurochemistry, ketamine is an nMDA antagonist - this means it acts on a specific type of neural receptor in the brain, the nMDA receptor, found throughout the brain but particularly in the cortex, and it act by suppressing its normal activity (whilst an agonist would boost it). This leads to an excessive release of the neurotransmitter glutamate. This lays a case for a possible harmful effect of ketamine: nMDA antagonists have been shown to disrupt long-term potentiation (the neural mechanism by which learning takes place in the brain). And the receptors are particularly heavily distributed in memory-critical areas such as the hippocampus and surrounding areas, which means adverse effects are likely to impact on memory.

Moreover, clinical reports document that being on ketamine produces symptoms very similar to those seen in schizophrenia. The similarities have been so striking as to contribute to a shift away from purely dopaminergic models of schizophrenia to nMDA hypofunction models, which suggest that glutamate as well as dopamine are responsible for the abnormal function of the schizotypic brain. (see e.g. Olney and Farber 1997).

Morgan and Curran have been investigating this using cognitive and neuropsychological testing, alongside clinical-style inventories of schizotypic symptoms and thoughts. One aspect of their research uses healthy people, dosed up with ketamine. Relative to doses of placebo, ketamine-addled subjects were impaired across a variety of tasks - short-term memory, attention, and problem solving. They also gave higher ratings when asked to score a number of schizophrenic-type experiences, such as such as 'The world does not feel real to me'.

Anyone investigating specific populations (like patients, drug users or people with developmental disorders), rather than imposing different conditions on a generic population, will tell you nightmares of exclusion criteria, control group selection and so on. The difficulty with ketamine users is that they invariably take a lot more than ketamine - cocaine, weed, ecstacy and even more obscure drugs. Their solution was to accept poly-drug users in the ketamine group - and to match with a control group of poly-drug users, who had never done ketamine. In effect, this is a subtraction technique, similar to the kind that underlies many imaging studies (activation difference between complex and baseline tasks shows you the activation due to the processes unique to the complex task), and underlies much of the presuppositions of cognitive neuropsychology.

Compared to this control group, ketamine users were poorer on days following their drug intake, and still poorer three days afterward. As ketamine has a very short half-life, it seems fair evidence that this may represent neural degeneration (already established in laboratory work - Olney et al 1998), rather than active effects of the drug. (To make sure of this, they also compared subjects from their non-chronic use experiment after three days, and the placebo and ketamine group were not performing at different levels.) Their poorer performance was shown on tests of source memory, story recall, verbal fluency (being able to list words of a specific criteria rapidly) and speed of semantic processing (what things mean). They also, needless to say, showed higher ratings of schizotypic type symptoms. A follow-up study on a sample of former chronic users is also a window into how enduring these effects are; changes in certain measures were heavily correlated with changes in ketamine intake, but many others, including the schizotypic symptoms, continued to persevere. What is perhaps the most ominous of the findings is the apparent irreversability of the impairment produced in episodic memory (personal memories of events and instances), and possibly also attention.

Abstract of paper on healthy individuals linkAbstract of longitudinal paper in Addiction link

*Non-UK readers, insert your own amusing locations (to wit: lively if rough urban area; rural dull spot; corner-store-cum-supermarket). Once you have done this, laugh appreciatively, and wonder at the marvel of international collaboration. Truly, is there nothing we cannot do?

** I hasten to add that Special K the cereal is not in any way hallucinogenic, unless you can hallucinate from eating damn fine flakes. Of maize!